Reticulon-4 (RTN4), commonly known as a neurite outgrowth inhibitor (Nogo), is emerging as an important player in human cancers. Clinically, we found lower RTN4 expression in patient-derived tumors was associated with significantly better survival in lung, breast, cervical, and renal cancer patients. To identify the role of RTN4 in cancer biology, we performed mass spectrometry-based quantitative proteomic analysis on cancer cells following RTN4 knockdown and found its link with pro-survival as well as cytoskeleton-related processes. Subsequent mechanistic investigations revealed that RTN4 regulates lipid homeostasis, AKT signaling, and cytoskeleton modulation. In particular, downregulation of RTN4 reduced sphingomyelin synthesis and impaired plasma membrane localization of AKT, wherein AKT phosphorylation, involved in many cancers, was significantly reduced without any comparable effect on AKT-related upstream kinases, in a sphingolipid-dependent manner. Furthermore, knockdown of RTN4 retarded proliferation of cancer cells in vitro as well as tumor xenografts in mice. Finally, RTN4 knockdown affected tubulin stability and promoted higher cytotoxic effects with chemotherapeutic paclitaxel in cancer cells both in vitro and in vivo. In summary, RTN4 is involved in carcinogenesis and represents a molecular candidate that may be targeted to achieve desired antitumor effects in clinics.

Reticulon-4（RTN4）通常被称为神经突增生抑制剂（Nogo），正在成为人类癌症中的重要角色。在临床上，我们发现患者源性肿瘤中较低的RTN4表达与肺癌，乳腺癌，宫颈癌和肾癌患者的生存率显着提高相关。为了确定RTN4在癌症生物学中的作用，我们对RTN4敲低后的癌细胞进行了基于质谱的定量蛋白质组学分析，发现其与促存活以及与细胞骨架相关的过程有关。随后的机理研究表明，RTN4调节脂质稳态，AKT信号传导和细胞骨架调节。特别是，RTN4的下调会降低鞘磷脂的合成和AKT的质膜定位受损，其中AKT磷酸化与许多癌症有关，以鞘脂依赖的方式显着降低了Aβ的表达，而对AKT相关的上游激酶没有任何可比的影响。此外，敲低RTN4可以抑制癌细胞的增殖体外以及小鼠体内的肿瘤异种移植。最后，RTN4敲低影响了微管蛋白的稳定性，并在体外和体内用化疗紫杉醇促进了较高的细胞毒性作用。总而言之，RTN4参与致癌作用，代表一种分子候选物，可在临床上靶向达到所需的抗肿瘤作用。